Giving a Voice to Patients With Smell Disorders Associated With COVID-19: Cross-Sectional Longitudinal Analysis Using Natural Language Processing of Self-Reports.

BACKGROUND: Smell disorders are commonly reported with COVID-19 infection. The smell-related issues associated with COVID-19 may be prolonged, even after the respiratory symptoms are resolved. These smell dysfunctions can range from anosmia (complete loss of smell) or hyposmia (reduced sense of smell) to parosmia (smells perceived differently) or phantosmia (smells perceived without an odor source being present). Similar to the difficulty that people experience when talking about their smell experiences, patients find it difficult to express or label the symptoms they experience, thereby complicating diagnosis. The complexity of these symptoms can be an additional burden for patients and health care providers and thus needs further investigation. OBJECTIVE: This study aims to explore the smell disorder concerns of patients and to provide an overview for each specific smell disorder by using the longitudinal survey conducted in 2020 by the Global Consortium for Chemosensory Research, an international research group that has been created ad hoc for studying chemosensory dysfunctions. We aimed to extend the existing knowledge on smell disorders related to COVID-19 by analyzing a large data set of self-reported descriptive comments by using methods from natural language processing. METHODS: We included self-reported data on the description of changes in smell provided by 1560 participants at 2 timepoints (second survey completed between 23 and 291 days). Text data from participants who still had smell disorders at the second timepoint (long-haulers) were compared with the text data of those who did not (non-long-haulers). Specifically, 3 aims were pursued in this study. The first aim was to classify smell disorders based on the participants' self-reports. The second aim was to classify the sentiment of each self-report by using a machine learning approach, and the third aim was to find particular food and nonfood keywords that were more salient among long-haulers than those among non-long-haulers. RESULTS: We found that parosmia (odds ratio [OR] 1.78, 95% CI 1.35-2.37; P<.001) as well as hyposmia (OR 1.74, 95% CI 1.34-2.26; P<.001) were more frequently reported in long-haulers than in non-long-haulers. Furthermore, a significant relationship was found between long-hauler status and sentiment of self-report (P<.001). Finally, we found specific keywords that were more typical for long-haulers than those for non-long-haulers, for example, fire, gas, wine, and vinegar. CONCLUSIONS: Our work shows consistent findings with those of previous studies, which indicate that self-reports, which can easily be extracted online, may offer valuable information to health care and understanding of smell disorders. At the same time, our study on self-reports provides new insights for future studies investigating smell disorders.

Impairment of Hypnosis by Nocebo Response and Related Neurovegetative Changes: A Case Report in Oral Surgery.

This article presents the third molar removal in a highly hypnotizable patient, who had been successfully submitted to oral surgery with hypnosis as stand-alone anesthesia in previous sessions. Unexpectedly, hypnosis initially failed, as a result of a nocebo response due to a previous dentist's bad communication; two complaints made by the patient were associated with increased sympathetic activity (as defined by increased heart rate and electrodermal activity and decreased heart rate variability). After deepening of hypnosis, the patient achieved a full hypnotic analgesia allowing for a successful conclusion of the intervention, an event associated with decreased heart rate, electrodermal activity, and increased heart rate variability. Hence, the initial failure was paralleled by a decreased parasympathetic activity and increased sympathetic activity, while hypnotic analgesia was associated with the opposite pattern. The patient's postoperative report indicated that the initial failure of hypnosis depended on a strong nocebo effect because of a previous dentist distrusting hypnosis and persuading her that it was not enough to face a third molar removal.

Persistent and transient olfactory deficits in COVID-19 are associated to inflammation and zinc homeostasis.

Introduction: The Coronavirus Disease 2019 (COVID-19) is mainly a respiratory syndrome that can affect multiple organ systems, causing a variety of symptoms. Among the most common and characteristic symptoms are deficits in smell and taste perception, which may last for weeks/months after COVID-19 diagnosis owing to mechanisms that are not fully elucidated. Methods: In order to identify the determinants of olfactory symptom persistence, we obtained olfactory mucosa (OM) from 21 subjects, grouped according to clinical criteria: i) with persistent olfactory symptoms; ii) with transient olfactory symptoms; iii) without olfactory symptoms; and iv) non-COVID-19 controls. Cells from the olfactory mucosa were harvested for transcriptome analyses. Results and discussion: RNA-Seq assays showed that gene expression levels are altered for a long time after infection. The expression profile of micro RNAs appeared significantly altered after infection, but no relationship with olfactory symptoms was found. On the other hand, patients with persistent olfactory deficits displayed increased levels of expression of genes involved in the inflammatory response and zinc homeostasis, suggesting an association with persistent or transient olfactory deficits in individuals who experienced SARS-CoV-2 infection.

Anxiety in a regular day of work: A 24 hour psychophysiological investigation in young dentists with gender comparison.

Introduction and aim: Dentistry is a highly demanding profession with a strong mental and physical involvement, possibly generating anxiety. Very few studies assessed psychophysiological activity in dentists, while none tried to relate it with gender during a routine working day. This study aims at evaluating correlations between gender, psychophysiological indexes, and psychological variables. Materials and methods: Data were acquired at the Dental Clinic of the University of Padua on 20 healthy young dentists (10 M-10F) during a 24 h period of a working day. Physiological variables (measured with E4 Empatica) were electrodermal activity (EDA), heart rate variability (HRV) and heart rate (HR). Participants anxiety was measured through a self-reported scale on patient-relationship anxiety and through the Generalized Anxiety Disorder-7 Questionnaire (GAD-7). Results: 5 (3F, 2 M) participants over 20 had a GAD-7 score ≥ 10. Female gender, in comparison to Male, was associated with higher perceived patient relationship anxiety (p = 0.002) and lower HRV (p-adj = 0.022). The gender Male, although being associated with lower level of self-reported anxiety (p = 0.002), showed an equal number of subjects with a GAD-7 score ≥ 10 (p = 0.371). No interaction between gender and EDA was found, nor an effect of GAD score on EDA, HRV and HR values. Higher values of EDA were found during sleep time; a difference between sleep time and working time EDA (p = 0.037) and a difference between sleep time and daytime (p = 0.0045). A different HR between sleep and all daytime (p < 0.001) was also highlighted. Conclusion: 25% of dentists fell within generalized anxiety disorder diagnosis, compared to a maximum of 8.6% in the general population. A possible general biomarker of excessive stress response was measured: a shift of circadian sympathetic activity was found in dentists; a higher activity during sleep in comparison to working time and daytime. The Female gender was associated with higher perceived patient-approach anxiety, lower parasympathetic activity, and a comparable sympathetic activity to the Male gender, thus fostering a possible vulnerability to excessive stress. This study underlines the need to empower the psychological approach to stress and patient-relationship in dentistry.

Genomic surveillance of SARS-CoV-2 in patients presenting neurological manifestations.

During the first wave of infections, neurological symptoms in Coronavirus Disease 2019 (COVID-19) patients raised particular concern, suggesting that, in a subset of patients, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could invade and damage cells of the central nervous system (CNS). Indeed, up to date several in vitro and in vivo studies have shown the ability of SARS-CoV-2 to reach the CNS. Both viral and/or host related features could explain why this occurs only in certain individuals and not in all the infected population. The aim of the present study was to evaluate if onset of neurological manifestations in COVID-19 patients was related to specific viral genomic signatures. To this end, viral genome was extracted directly from nasopharyngeal swabs of selected SARS-CoV-2 positive patients presenting a spectrum of neurological symptoms related to COVID-19, ranging from anosmia/ageusia to more severe symptoms. By adopting a whole genome sequences approach, here we describe a panel of known as well as unknown mutations detected in the analyzed SARS-CoV-2 genomes. While some of the found mutations were already associated with an improved viral fitness, no common signatures were detected when comparing viral sequences belonging to specific groups of patients. In conclusion, our data support the notion that COVID-19 neurological manifestations are mainly linked to patient-specific features more than to virus genomic peculiarities.

Altered brain regional homogeneity is associated with depressive symptoms in COVID-19.

BACKGROUND: COVID-19 is an infectious disease that has spread worldwide in 2020, causing a severe pandemic. In addition to respiratory symptoms, neuropsychiatric manifestations are commonly observed, including chronic fatigue, depression, and anxiety. The neural correlates of neuropsychiatric symptoms in COVID-19 are still largely unknown. METHODS: A total of 79 patients with COVID-19 (COV) and 17 healthy controls (HC) underwent 3 T functional magnetic resonance imaging at rest, as well as structural imaging. Regional homogeneity (ReHo) was calculated. We also measured depressive symptoms with the Patient Health Questionnaire (PHQ-9), anxiety using the General Anxiety Disorder 7-item scale, and fatigue with the Multidimension Fatigue Inventory. RESULTS: In comparison with HC, COV showed significantly higher depressive scores. Moreover, COV presented reduced ReHo in the left angular gyrus, the right superior/middle temporal gyrus and the left inferior temporal gyrus, and higher ReHo in the right hippocampus. No differences in gray matter were detected in these areas. Furthermore, we observed a negative correlation between ReHo in the left angular gyrus and PHQ-9 scores and a trend toward a positive correlation between ReHo in the right hippocampus and PHQ-9 scores. LIMITATIONS: Heterogeneity in the clinical presentation in COV, the different timing from the first positive molecular swab test to the MRI, and the cross-sectional design of the study limit the generalizability of our findings. CONCLUSIONS: Our results suggest that COVID-19 infection may contribute to depressive symptoms via a modulation of local functional connectivity in cortico-limbic circuits.

Drug-induced Parkinson's disease modulates protein kinase A and Olfactory Marker Protein in the mouse olfactory bulb.

BACKGROUND: Olfaction is often affected in parkinsonian patients, but dopaminergic cells in the olfactory bulb are not affected by some Parkinson-inducing drugs. We investigated whether the drug MPTP produces the olfactory deficits typical of Parkinson and affects the olfactory bulb in mice. FINDINGS: Lesioned and control mice were tested for olfactory search, for motor and exploratory behavior. Brains and olfactory mucosa were investigated via immunohistochemistry for thyrosine hydroxylase, Olfactory Marker Protein and cyclic AMP-dependent protein kinase as an intracellular pathway involved in dopaminergic neurotransmission. MPTP induced motor impairment, but no deficit in olfactory search. Thyrosine hydroxylase did not differ in olfactory bulb, while a strong decrease was detected in substantia nigra and tegmentum of MPTP mice. Olfactory Marker Protein decreased in the olfactory bulb of MPTP mice, while a cyclic AMP-dependent protein kinase increased in the inner granular layer of MPTP mice. CONCLUSIONS: MPTP mice do not present behavioural deficits in olfactory search, yet immunoreactivity reveals modifications in the olfactory bulb, and suggests changes in intracellular signal processing, possibly linked to neuron survival after MPTP.

Investigation of N-cadherin/ß-catenin expression in adrenocortical tumors.

ß-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound ß-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). ß-catenin mutations were evaluated by sequencing, and ß-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in ß-catenin gene. qRT-PCR showed overexpression of ß-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear ß-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. ß-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and ß-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line.

New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.

Mitogen-Activated Protein Kinase Pathway: Genetic Analysis of 95 Adrenocortical Tumors.

Mitogen-activated protein kinase (MAPK) pathway is often deregulated in adrenocortical tumors (ACT) but with no concrete data confirming alteration rate. The objective of this study was to evaluate genetic alterations in key components of MAPK pathway. We found one BRAF mutation (p.V600E) and four HRAS silent mutations. No alteration was found in NRAS, KRAS, EGFR genes. The patient carrying BRAF mutation was further characterized by investigating his biomolecular and clinico-pathological findings. Therefore, even if MAPK signaling is activated in ACT, our results suggest that genetic alterations do not seem to represent a frequent mechanism of ACT tumorigenesis.

Increased spontaneous activity of a network of hippocampal neurons in culture caused by suppression of inhibitory potentials mediated by anti-gad antibodies.

INTRODUCTION: Anti-glutamic acid decarboxylase autoantibodies (GAD-Ab) are commonly considered the marker of autoimmune diabetes; they were first described in patients affected by stiff-person syndrome and recently, in ataxic or epileptic patients. The pathogenetic role of GAD-Ab remains unclear but inhibition of GABA synthesis or interference with GABA exocytosis are hypothesized. The aim of the study was to assess whether GAD-Ab interfere with neuronal transmission. PATIENTS AND METHODS: Serum from a GAD-Ab positive epileptic patient (by IHC and RIA), serum from a GAD-positive (only by RIA) diabetic case, sera from two epileptic GAD-Ab negative patients and a normal control were selected. Post-synaptic inhibitory potentials (IPSPs) were registered on hippocampal neurons in culture before and after the application of diluted sera in a patch clamp study. RESULTS: A significant increase in the frequency of IPSPs was observed after application of GAD-positive epileptic serum, while no effect was noted using sera from negative controls. CONCLUSION: The inhibition in neuronal transmission only after application of GAD-positive epileptic serum, suggests an interference with GABA function and consequently with neuronal inhibition supporting a pathogenetic role of GAD-Ab in the development of epilepsy.

Peculiar labeling of cultured hippocampal neurons by different sera harboring anti-glutamic acid decarboxylase autoantibodies (GAD-Ab).

Immunological derangement is assumed to be present in a subgroup of patients affected by drug-resistant epilepsy with serum harboring anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). To further investigate the specific reactivity of GAD-Ab with target cells, we tested sera from drug-resistant epileptics harboring GAD-Ab on cultured fetal rat hippocampal neurons. As a control, we tested sera from GAD-Ab-negative epileptics and GAD-Ab-positive patients affected by Stiff Person Syndrome (SPS), ataxia or diabetes. A specific pattern of reactivity, varying according to disease, was detected on application of sera from GAD-Ab-positive patients with epilepsy, SPS and ataxia, but no specific labeling was found on application of sera from patients with GAD-Ab-negative epilepsy or from GAD-Ab-positive diabetic controls.

High-resolution magnetic resonance spectroscopy of the mouse vomeronasal organ.

The chemical composition of the vomeronasal organ (VNO) was investigated by means of in vitro proton magnetic resonance spectroscopy (MRS) in prepubertal and adult mice of both sexes. Results demonstrate that MRS detects several chemical constituents in the VNO, showing their age- and sex-associated changes in concentration. Preliminary experiments also suggest the ability of MRS to show compositional changes in the VNO after pheromonal stimulation. MRS can serve as a useful technique to investigate vomeronasal chemoreception.